Preparation of 2,3,4,5-tetrahydro-1H-3-benzazepines and 1,2,3,4,5,6-hexahydro-3-benzazocines

ABSTRACT

A process for the preparation of heterocyclic compounds containing one nitrogen atom and novel 2,3,4,5-tetrahydro-1H-3benzazepines prepared by this process are disclosed. The resulting heterocyclic compounds, including the novel 2,3,4,5tetrahydro-1H-3-benzazepine derivatives, exhibit analgesic, appetite suppressant, and anti-edema activity.

United States Patent [191 Brossi et al.

[4 1 Sept. 16, 1975 [5 PREPARATION OF 2,3,4,5-TETRAHYDRO-lH-3-BENZAZEPINES AND l,2,3,4,5,6-HEXAHYDRO-3-BENZAZOCINES [75} Inventors:Arnold Brossi, Verona; Benjamin Pecherer, Montclair; Robert Sunbury,Way'ne, all of NJ.

[73] Assignee: Hoffmann-La Roche Inc., Nutley,

[22] Filed: Oct. 1, 1973 [21] Appl. No.'. 402,536

Related US. Application Data [62] Division of Scr. No. 65,340, Aug. 19,1970, Pat. No.

[52] US. Cl..... 260/340.5; 260/239 BB; 260/326 R; 260/465 D; 260/47] R;260/51 8 R; 260/518 A; 260/562 R [51] Int. Cl ..C07D 223/16; C071)225/06;

C07D 317/62 [58] Field of Search 260/340.5, 239 BB [56] References CitedUNITED STATES PATENTS 2,485,600 10/1949 Hedcnburg 260/340.5 X

2,878,266 3/1959 Wachs et al. 260/340.5

OTHER PUBLICATIONS Primary Examiner-Anton H. Sutto AssistantExaminerMichael Shipper Attorney, Agent, or FirmSarnuel L. Welt; BernardS. Leon; Frank P. Hoffman 57 ABSTRACT A process for the preparation ofheterocyclic compounds containing one nitrogen atom and novel 2,3,4-S-tetrahydro-l H-3-benzazepines prepared by this process are disclosed.The resulting hcterocyclic compounds, including the novel2,3,4,5-tetrahydro-lH-3- benzazepine derivatives, exhibit analgesic,appetite suppressant, and anti-edema activity.

1 Claim, No Drawings PREPARATION OF2,3,4,S-TETRAHYDRO-lH-S-BENZAZEIINESv ANDl,2,3,4,5,6rHEXAHYDRO-Ii-BENZAZOCINES This is a division of applicationSer. No. 65,340 filed Aug. 19, 1970 now US. Pat. No. 3,795,683,.

DESCRIPTION OF THE INVENTION The present invention relates to a processfor preparing compounds of pharmacological value and to novelintermediates and end products resulting from this process. Moreparticularly, the present invention relates to a process for thepreparation ofmedium sized heterocyclic compounds containing onenitrogen atom, i.e., compounds of the formula:

tives (hereinafter referred to as 3-benzazepines). Among the preferrednovel 3-benzazepines prepared according to this invention are thosewherein the wherein R signifies hydrogen or; halogen; R and R eachindependently signify lower alkyl or lower alkoxy, or taken togethersignify methylenedioxy; R signifies hydrogen, lower alkyl, carboxy,aryl, or aryl substituted by a member selected from thegroup consistingof halogen, lower alkyl, nitro or trifluoromethyl; R signifies hydrogen,benzyl, lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl,halo-lower alkyl carbonyl, aminolower alkyl carbonyl, mono-loweralkylamino-lower alkylcarbonyl, di-lower alkylamino-lower alkylcarbonyl, lower alkenyl, amino-lower alkyl, mono-lower alkylamino-loweralkyl, di-lower alkylamino-lower alkyl, carboxy-lower alkyl,carbalkoxy-lower alkyL'di-lower alkyl amino-carbonyl-lower alkyl,benzoyl-lower alkyl, halo-benzoyl-lower alkyl, or the group, COCH Rwherein R signifies phenyl or phenyl substituted by a member of thegroup consisting of halogen, lower alkyl, nitro and trifluoromethyl; nis 1 or t 2; and B is -CH- ,or CO and 'pharmaceutically acceptable acidaddition salts thereof.

As used throughout this disclosure the term halogen" denotes all fourforms thereof, i.e., chlorine, fluorine, bromine and iodine unlessotherwise specified. The term lower alkyl includes straight and branchedchain hydrocarbon groups having from 1 to 7, preferably 1 to 4 carbonatoms including, for example, methyl, ethyl, propyl, isopropyl, butylandthe like. Likewise. the term lower alkenyl includes straight andbranched chain olefinic unsaturated hydrocarbon groups having from 2 to7, preferably from 2 to 4 carbon atoms. The phrase carbalkoxy" signifiesthe grouping COOlower alkyl. The expression halolower alkyl" includesmono as well as diand tri-halo lower alkyl groups. The term aryl denotesan organic radical derived from an aromatic hydrocarbon by the removalof a hydrogen atom. The term 'acyl is intended to denote an organicradical derived by removal of (a) hydroxyl group(s) from an organicacid(s).

The process of the present invention results in. the preparation of manynovel heterocyclic compounds, including, of particular interest, manyheretofor unknown 2,3,4,5-tetrahydro-lH 3-benzazepine derivaphenyl ringbears a methylenedioxy group in positions 7,8. Another preferred groupof novel 3-benzazepines prepared following the inventive procedureconsists of compounds showing substitution on the 3-nitrogen. Ofparticular interest among the novel 3-benzazepines of this invention arecompounds of the formula:

wherein R and R are as d escribcdabove and pharmaceutically acceptableacid addition salts thereof. The 3-benzaZepines of formula II above arenovel and as such form a part of the present invention.

The numbering of the 3-benzazepine ring system used in this disclosureis shown in formula ll above.

A preferred class of compounds falling within the scope of formula IIabove are those wherein R signifies hydrogen, lower alkyl, hydroxy-loweralkyl, aminolower alkyl, mono-lower alkyl-amino-lower alkyl and di-loweralkylamino-lower alkyl, i.e., compounds of the formulaz N-R II-a IIbwherein R is as described above and R signifies lower alkyl, halo-loweralkyl, amino-lower alkyl, mono-lower alkylamino-lower alkyl, di-loweralkylamino-lower alkyl and the group Cl-l R R being defined as above andpharmaceutically acceptable acid addition salts thereof.

In a further preferred aspect of the present invention, R signifieshydrogen and R signifies hydrogen, lower alkyl, or lower alkenyl.

Most preferred of the compounds of formula ll are:

2,3 ,4,5-tetrahydro-7,8-methylenedioxyl H-3- benzazepine;

2,3,4,5-tetrahydro-3-methyl-7,8methylenedioxylH-3 -benzazepine;

3-ethyl-2,3,4,5-tetrahydro-7,8-methylcnedioxy-1H- 3-benzazepine; and

3-allyl-2,3,4,5,tetrahydro-7,8-methylencdioxy-l H- 3-benzazepine.

Compounds of formula 1 above wherein B signifies a CH group, includingthe novel 3-bcnzazepines of formula ll, form pharmaceutically acceptableacid addition salts with pharmaceutically acceptable organic orinorganic acids. Suitable acids for this purpose including hydrochloricacid, phosphoric acid, hydrobromic acid, citric acid, sulfuric acid,succinic acid, maleic acid, p-toluenesulfonic acid, tartaric acid, andthe like.

The compounds of formula I above and the preferred novel 3-benzazepinesof formula [I above can be prepared following a variety of syntheticroutes, including the novel process aspect which forms a part of thepresent invention.

In following the aforementioned novel process aspect of this invention,the compounds of formula 1 above may be prepared by thechloromethylation of a compound of the formula R (CH )n Y NH-X R 2wherein R R X and n are as described above.

The chloromethylation is carried out using special reaction conditionswhich effect the introduction of the CH Cl group directly into thearomatic compound of formula III via the interaction of said formula IIIcompound with formaldehyde and hydrogen chloride. The chloromethylationreaction is expediently effected in the presence of an inert organicsolvent such as a halogenated hydrocarbon, for example, ethylenechloride, tetraehloroethane and the like, or acetic acid. It should benoted that the starting materials of formula III above bear substituentson the aromatic portion of the molecule which direct the incomingchloromethyl group to the position ortho to the acylamido-lower alkylside chain.

The chloromethylated compound of formula IV above is then converted tothe corresponding cyanomethylated compound of the formula 3 (CHZZJII 4NHX R CH CN wherein R -R X and n are as described above.

The conversion of the chloromethyl group of the compounds of formula IVto the cyanomethyl group of the compounds of formula V can beaccomplished, for example, by treating the compounds of formula IV withan alkali metal cyanide, preferably sodium or potassium cyanide. Theconversion of the compounds of formula lV above to the compounds offormula V is expediently effected in the presence of an aprotic polarsolvent such as dimethylsulfoxide (DMSO), N,N-dime thylformamide (DMF)and the like, with DMSO being preferred,

The so-obtained cyanomethyl compound of formula V is then converted tothe corresponding ethyl ester compound of the formula R cH.,cooE1wherein R R X and n are as described above.

The conversion of the compound of formula V above to the correspondingester compound of formula VI can be accomplised following standardtechniques, such as, by alcoholyzing the nitrile of formula V.Alcoholysis of the nitrile can be effected by refluxing the nitrile inabsolute alcohol and anhydrous acid, preferably hydrochloric acid, toobtain the imido ester salt, with subsequent addition of water to obtainthe ester. This alcoholysis can also be accomplished by dissolving thecyanomethyl derivative in a mineral acid saturated ethanol solution.Suitable mineral acids used in preparing the saturated alcohol solutionare hydro-halic acids such as hydrogen chloride and hydrogen bromide orsulfuric acid.

The so-obtained ester compound of formula V1 is then hydrolyzed to thecorresponding acetic acid compound of the formula Vll wherein R -R X andn are as described above.

The hydrolysis of the ester compound of formula VI to the correspondingacid of formula VII may be accomplished, for example, by treating theester in an aqueous solution containing either acidic or basiccatalysts. Suitable acid catalysts for this purpose include hydrochloricacid, sulfuric acid and the like while suitable basic catalysts includealkali and alkaline earth metal hydroxides such as sodium hydroxide,potassium hy droxide, calcium hydroxide and the like.

The nitrogen protecting group present in the so obtained acetic acidcompound of formula Vll above is then split off to yeild thecorresponding amino acid compound of the formula VIII NH R CH COOHwherein R R and n are as described above.

The splitting off of the protecting group may be accomplished usingconventional techniques. Thus, for example, if the protecting grouputilized is an acyl group, the desired amino acid compound of formulaVIII can be obtained by de-acylation of the formula VII compound. Thisde-acylation can be effected by heating the formula VII compound in anacid or alkaline solution. Suitable acids for this purpose includehydrochloric acid, sulfuric acid and the like, suitable bases includesodium and potassium hydroxide. Likewise, if the protecting grouputilized is a phthaloyl group, this can be split off by alkalinetreatment of the formula VII compound, preferably with sodium hydroxide,or by hydrazinolysis, preferably with hydrazine hydrate.

In the next step of this process, the amino acid compound of formulaVIII above is condensed to the corresponding compound of formula Iwherein B signifies CO-. The lactam thus obtained can be represented bythe following formula (CH )n R wherein R R and n are as described aboveand R signifies hydrogen, benzyl, or lower alkyl.

The conversion of the amino acid compound of formula VIII above to thecorresponding lactam of formula Ia may be accomplished following avariety of procedures. For example, thermal treatment of the compound offormula VIII will effect condensation of said compound to the desiredlactam. This thermal condensation is expediently effected usingtemperatures above room temperature, and is most preferably effected atthe reflux temperature of the reaction medium. It is expedient toconduct the thermal condensation in the presence of a high boiling pointsolvent which is capable of forming an azeotropic mixture with water.Suitable solvents for this'purpose include tetralin, xylene and thelike. In cases where the lactam is formed via thermal condensation, itis preferable to first form the secondary amine derivative of thecompound of formula VIII since condensation occurs more readily usingsaid compound. The benzyl derivative, which can be represented by theformula VIII-a wherein R -R and n are as described above may beprepared, for example, by treating the amino acid derivative of formulaVIII with benzaldehyde in the presence of sodium borohydride. If thebenzyl derivative of formula Vllla above is utilized, the lactamobtained upon thermal condensation will bear a benzyl group substitutedon the nitrogen atom.

Alternately, conversion of the amino acid compound of formula VIII tothe lactam of formula la wherein R is hydrogen can be accomplished bytreating a solution of the amino acid compound with a condensing agentsuch as l-cyclohcxyl-3-(2-morpholinoethyl)carbodiimidemethotoluenesulfonate to yield the desired lactam. Temperature is notcritical to this process aspect and for the sake of convenience thecondensation is expediently effected at room temperature.

Thelactam of formula la above is then reduced to the correspondingcompound of formula I wherein B signifies -CH i.e., to a compound of theformula Wherein R R R and n are as described above. The reduction of thelactam of formula Ia to the corre sponding compound of formula lb can beaccomplished using conventional reduction techniques. For example, thecarbonyl group can be reduced to the desired meth ylene group bytreating a compound of formula Ia above with a suitable reducing agentsuch aslithium aluminum hydride, lithium borohydride, borane and thelike.

If desired, the compound of formula Tb wherein R signifies benzyl can bedebenzylated using standard catalytic dehydrogenation techniques.Substituents can be introduced onto the nitrogen atom in theheterocyclic ring system after reduction and debenzylation of theformula Ia compound. This substitution of the nitrogen atom can beaccomplished following a variety of procedures, depending upon thenature of the group being introduced. Thus, for example, a lower alkylor substituted lower alkyl group can be introduced using standardalkylation procedures while an acyl or substituted acyl group can beintroduced using standard acylation techniques. Additional details as tothe introduction of substituents on the heterocyclic ring system arepresented hereinbelow.

The compounds of formula III above used as starting materials in theabove described process are known or can be prepared in analogy to thepreparation of the known compounds. 1

In addition to the novel process aspect described above, the2,3,4,5-tetrahydro-l H3-benzazepines of formula ll above wherein Rsignifies hydrogen can be prepared by the catalytic hydrogenation of acompound of the formula CH CN CH CN in the presence of ammonia using anickel catalyst such as Raney nickel. The catalytic hydrogenation of thecompound of formula IX results in the formation of the benzazepine ofthe formula This hydrogenation procedure is preferably effected in thepresence of an inert organic solvent such as metha nol, ethanol and thelike.

The 3-acetyl derivative can be prepared by acetylation of the compoundof formula llc. This acetylation produces the compound of the formulaThe compounds of formula ll above wherein R signifies halogen can beprepared by halogenation of the compound of formula Ild, for example bybromination with bromine in acetic acid or by chlorination withchlorine.

The compounds of formula ll above wherein R signifies a lower alkyl, alower alkenyl, or a substituted lower alkyl group such as a di-loweralkyl-amino-lower alkyl group can be prepared by the alkylation of thecompound of formula llc above. This alkylation is preferablyaccomplished by first forming the N-sodio derivative of the compound ofHe and then treating this N- sodio derivative with an alkylating agentsuch as an alkyl halide, alkyl sulfate, alkenyl halide, and the like.The N-sodio derivative of llc can be prepared by heating the formulallc' compound with sodium hydride.

The compounds of formula II above wherein R signifies carbalkoxy-loweralkyl can be prepared by reacting the N-sodio derivative of the compoundof formula llc with a compound of the formula halo-(CH ),,,COO-loweralkyl wherein m is an integer from 1-7.

The reaction between the N-sodio derivative of lIc and a compound offormula X is expediently effected in the presence of an inert organicsolvent such as dimethylformamide.

The compounds of formula ll above wherein R signifies carboxy-loweralkyl can be prepared by hydrolysis of the corresponding esterderivative, i.e., the corresponding compound wherein R signifiescarbalkoxylower alkyl. The hydrolysis can be effected by treating theester derivative with a solution of an alkali metal hydroxide,preferably sodium hydroxide, in water. The reaction is expedientlyeffected in the presence of an inert organic solvent such as methanol,ethanol and the like.

The compounds of formula llb above may be prepared by reacting thecompound of formula Ilc above with a compound of the formula halo--CR orO(CR ,)2 XI wherein R is as described above.

The reaction of the compound of formula llc with a compound of formulaX1 is expediently effected in the presence of an inert organic solventsuch as an aromatic hydrocarbon, for example, benzene, toluene and thelike.

The compounds of formula 1 above and their pharmaceutically acceptableacid addition salts exhibit analgesic, appetite suppressant andantiedema activity. Their useful analgesic activity is shown inwarmblooded animals utilizing for example a test which is a modificationof that described by Eddy (1950), Wolfe and MacDonald 1944) and Eddy andLeimbach (1952). The method determines the reaction time of mice droppedonto a hot plate maintained at 55: O.5C. Six groups of male mice (5mice/group) weighing between 2030 grams are utilized. The initial reaction time of these mice is determined once, and the reaction time ofeach group is then averaged. The mice are then administered the vehicleand/or the compound to be tested by the oral, intraperitoneal orsubcutaneous route. The average reaction time of each group isdetermined again at 30, 60 and minutes after compound administration andis compared to controls. Reaction time is recorded as percent changesfrom control. All groups are averaged before and after treatment. Acombined reaction time average (recorded as percent change of reactiontime threshhold from controls) for all three periods is plotted againstdose on graph paper, anda curve is drawn. The ED is read from thiscurve. I

Utilizing this standard procedure, compounds such as 1,2,3,4,5,6-hexahydro-8,9-methylenedioxy-3- benzazocine (Compound A),2,3,4,5tetrahydro-7,8- dimethyl-1l-l-3-benzazepine (Compound B) y and7,8- methylenedioxy-2,3 ,4,5-tetrahydrol H-3-benzazepine (Compound C)show an ED of 200 mg., 6 mg., and 200 mg. respectively.

The appetite suppressant activity of the compounds of formula l isdemonstrated in warm-blooded animals utilizing a standard anti-obesitytest. In this test, six groups of five female rats each are weighed andstarved for 24 hours. The animals are arranged so that each group hasthe same total weight. A dose of the test compound in distilled water isadministered subcutaneously, the body weight recorded and a known weightof food pellets given. After4hours, the-animals and food DOSE, AR.Compound Food Eaten Weight Gained Water Drunk Compound A 27 mg. 20 mg.33 mg. Compound B 1 mg. 1 mg. 1 mg. Compound C 8 mg. 6 mg.

The anti-edema activity of the compounds of formula I is demonstrated inwarm-blooded animals utilizing a standard anti-edema test. In this test,60 male albino rats are given 10 ml. per kilogram of body weight ofvehicle containing, for the treatment groups, the test compound. Wateris given to bring the total volume to ml. in each animal. One hour later0.05 ml. ofa l per cent type No. 7 carrageenan in normal solution is injected into the right hind paw of the rat. The paw volume is measuredimmediately after the injection of the phlogistic agent and again 3hours later. The difference is recorded as volume of edema and the doserequired to produce a 30 per cent reduction in edema is estimated.Utilizing this standard procedure, compounds A, B and C above show an EDof 78 mg., 3.6 mg, and 12 mg. respectively.

The compounds of formula I can be used together with conventionalpharmaceutical carriers suitable for parenteral, or enteraladministration such as, for example water, gelatin, starch, magnesiumstearate, petroleum jelly and the like. They can be administered inconventional pharmaceutical forms, for example, solid forms such ascapsules, tablets, liquid forms such as solutions or emulsions.Moreover, the pharmaceutical compositions containing compounds offormula I can be subjected to conventional pharmaceutical expedientssuch as sterilization, and can contain conventional pharmaceuticalexcipients such as preservatives, stabilizing agents, wetting agents,emulsifying agents, salts for the adjustment of osmotic pressure, orbuffers. The compositions can also contain other therapeutically activematerials.

A suitable pharmaceutical dosage unit can contain from about 1 to about500 mg of the aforesaid compounds of formula I; with a dosage range offrom about I mg to about 100 mg being the preferred oral administrationand a dosage range of from about 1 mg to about 50 mg being preferred forparenteral administration. However, for any particular subject, thespecific dosage regimen should be adjusted according to individual need.It is to be understood that the dosages set forth herein are exemplaryonly and that they do not, to any extent, limit the scope or practice ofthis invention.

A The following examples further illustrate the invention. Alltemperatures are in degrees centigrade unless otherwise indicated.

In a 100 ml round-bottom flask provided with a stirrer, thermometer, gasinlet tube, and a condenser were placed 4.12 g ofN-acetyl-homopiperonylamine (0.02 mole), 2.1 g of 37% formaldehydesolution, and 50 ml of ethylene chloride. The mixture was cooled to 3and hydrogen chloride passed into the stirred mixture. After about 15minutes a thick paste of crystals had formed. At this point, another 2.1g of 37% formaldehyde was added and the mixture allowed to stir untilall the solid had dissolved. The solution was then poured into ice waterand the lower ethylene chloride layer separated, washed three times withwater, then dried. The clear ethylene chloride solution was freed ofsolvent in the rotary evaporator, leaving the above-named product as acrystalline solid. After recrystallization from acetone, the solidmelted at 1 l6.5l22.

EXAMPLE 2 Preparation of N-( 6-Cyanomethyl-3 ,4'methylenedioxyphenethyl)acetamide 4.7 g of N-(6-chloromethyl-3,4-methylenedioxyphenethyl)acetamide was dissolved in 10 ml of DMSO and 1.32 g (0.028 mole) ofsodium cyanide added to the stirred solution. Within a few minutes, thetemperature rose from 25 to 32C. After 1.5 hrs at ambient temperaturethe mixture was poured into ice and water. The suspension was extractedwith three 50-ml portions of benzene. The benzene layers were washedwith saturated brine six times, then with water, the solution dried, andthe solvent distilled in the rotary evaporator leaving the above-namedproduct as a crystalline solid, m.p. l5'3.3l55.5.

EXAMPLE 3 Preparation of Ethyl ester of6-(2-acetamidoethyl)-3,4-methylenedioxyphenylacetic acid 2.58 g (0.0104moles) of N-(6-cyanomethyl-3,4- methylenedioxyphenethyl) acetamide wasdissolved in 30 ml of ethanol saturated with hydrogen chloride. Aftersix hrs at 25, the mixture was poured into ice and water. The ester wascollected by extraction with benzene (3 X 25 ml), the benzene extractswashed successively with water, saturated bicarbonate solution, andwater, then dried. Distillation of the solvent gave a mass of longprismatic needles. These were recrystallized once from a mixture ofethanol and petroleum ether (b.p. 6090) to yield the above-namedproduct, m.p. 123-l25.

EXAMPLE 4 Preparation of 6-( 2-Acetamidoethyl )-3,4-methylenedioxyphenylacetic acid A small sample of the ethyl esterprepared in Example 3 was warmed on the steam bath in alcoholic solutionwith excess sodium hydroxide. The solution was brought to pH 9, aflocculent precipitate filtered off, and the clear filtrate acidified topH3. After standing overnight, clusters of crystals had separated. Thecrystals were recovered by filtration, washed with a little cold water,then recrystallized from a minimum of hot water to yield the above-namedproduct, m.p. l88l90.5.

EXAMPLE Preparation of 6-( 2-Amin0ethyl )-3,4-methylencdioxyphenylacetic acid hydrochloride One g of the acetamidoderivative prepared in Example 4 was refluxed with 20 ml of 4N HCl forhrs. The excess acid was removed on the rotary evaporator leaving asolid residue which was recrystallized from a mixture of isopropanol andethyl acetate to yield white crystals of the above-named product, rn.p.210212.

EXAMPLE 6 Preparation of6-(Z-Benzylaminoethyl)-3,4-methylenedioxyphenylacetic acid To a solutionof 26 g of the amino acid hydrochloride prepared in Example 5 (0.1mole), in 80 ml of water, was added 8.4 g of sodium hydroxide (0.21moles), in 42 ml of water, followed by 11.7 g (0.11 moles) ofbenzaldehyde. The initially turbid mixture immediately cleared. Afterone hour, the mixture was evaporated to a thick syrup on the rotaryevaporator, the syrup dissolved in 75 ml of ethanol, and the evaporationto syrup repeated. The residue was dissolved in 500 ml of methanol and6.5 g of sodium borohydride (0.17 moles) added in several portions.After stirring for 1.5 hours, the solvent was removed on the rotaryevaporator, leaving a grayish solid. This residue was dissolved in 200ml of water and 10 percent hydrochloric acid added to pH 7. Theprecipitate which formed was collected by filtration, washed with water,and dried to yield the abovenamed product, m.p. 217218 dec.

EXAMPLE 7 Preparation of The Lactone 24.7 g of the amino acid preparedin Example 6 was refluxed with 500 ml of xylene under a Dean-Stark trapfor seven hours. During this period, water was steadily collected andthe solid gradually dissolved. The clear solution was distilled in therotary evaporator leaving a crystalline residue, m.p. 141142. This wasrecrystallized from isopropanol to yield off-white crystals of3-benzyl-7,S-methylenedioxy-1,3,4,5-tetrahydro-2H-3- benzazepin-Z-one,m.p. l4l142.

Similarly, 0.005 moles (1.3 grams) of 6-(2-aminoethyl)-4,5-methylenedioxy phenylacetic acid hydrochloride weredissolved in ml of water and to this solution was added 2.12 grams ofl-cyclohexyl-3- (2-morpholinoethyl)carbodiimide methotoluenesulfonate inml of water. After 2 hours at room temperature the precipitate that hadformed was filtered off, washed and dried to yieldl,3,4,5-tetrahydro-7,8- methylenedioxy-ZH-3-benzazepin-2-one, mp. 236-237. After recrystallization from ether the product melted at 238239.

EXAMPLE 8 Preparation of d1- 1 3 ,4-Dimethyl-6-ch1oromethylphenyl )-2-acetamidopropane 4. 1 g of rac. l( 3,4-dimethylphenyl )-2-acetamidopropane was dissolved in 40 ml of 1,1,2,2- tetrachlorethane ina lOO-ml RB flask provided with a stirrer, thermometer, condenser, andgas inlet tube. Twelve ml of 37% formaldehyde was added, and a stream ofhydrogen chloride passed into the stirred mixture as the temperaturerose to 50, where it was maintained for 5 hrs. At this point, themixture remained overnight at room temperature. The reaction mixture waspoured into water, the organic phase was washed twice with water, dried,and the solvent distilled in the rotary evaporator, leaving 4.2 g of acolorless oil. The oil was refluxed with four l00-ml-portions ofpetroleum ether (b.p. 600), and from the com bined extracts, a mass ofcottony needles separated. The solid was collected by filtration andfreed of solvent in vacuo to yield the above-named product, m.p. 7273.

EXAMPLE 9 Preparation of d1-1-(3,4-Dimethyl-6-cyanomethylphenyl)-2-acetamidopropane Two g of the chloromethyl compound (0.0079 moles)prepared in Example 8 was dissolved in 20 ml of DMSO and 0.77 g (0.0119moles) of KCN added. The suspension was stirred and gradually warmed to45 over a period of 45 minutes, at which point the temperature suddenlyrose to 54, where it remained for some 5-7 minutes and then began tofall. After another 15 minutes, the reaction mixture was poured into icewater, the oil collected by three extractions with etherbenzene (50 mleach of a 1:1 mixture), the combined extracts washed with saturatedbrine, dried over MgSO and the solvents distilled in the rotaryevaporator. A white crystalline solid remained which was slurried in amixture of ethyl acetate and petroleum ether (b.p. 60-90), leaving theabove-named product as a solid, mp. 140l41.

EXAMPLE 10 Preparation ofdl-6-(2-Acetamid0propyl)-3,4-dimethylphenylacetic acid 7.1 g of thenitrile (0.03 mole) prepared in Example 9 and 75 ml of ethanol saturatedwith hydrogen chloride was stirred for one hour at room temperature,then refluxed for four hours. The cooled solution was poured into 500 m1of ice water and the aqueous solution extracted four times with SO-mlportions of chloroform. The combined chloroform extracts were washedwith water, dried (MgSO then distilled in the rotary evaporator to yieldthe ethyl ester of the above-named product as a pale yellowish oil.

This crude ethyl ester was refluxed with 25 ml of 10% sodium hydroxideand 25 ml of ethanol for one hour, then the ethanol distilled. Theresidue was cooled and the undissolved material removed by three washeswith benzene (25 ml each). The aqueous residue was then acidified to pH3 and extracted three times with SO-mlportions of chloroform. Theseextracts were washed with water, dried (MgSO distilled in the rotaryevaporator, to yield an oil which crystallized on standing overnight. Asample of this material was recrystallized from ethyl acetate andpetroleum ether (b.p. 60-90) to yield the above-named product as whitecrystals m.p. 6769.

EXAMPLE 1 1 Preparation of dl-6-(2-Aminopropyl)-3,4-dimethylphenylaceticacid 0.5 g of the acetamido acid prepared in Example 10 was refluxed for18 hours with 20 ml of 6N hydrochloric acid. The excess acid was removedin the rotary evaporator, leaving a semisolid residue. This wasdissolved in five ml of water and sodium bicarbonate solution added topH 6-7, whereupon a voluminous white precipitate formed. After chillingfor an hour, the solid was recovered by filtration and recrystallizedfrom aqueous ethanol. The white crystals of the abovenamed product thusobtained melted at 222.5223 with decomposition.

EXAMPLE 12 Preparation of dl-4,7,8Trimethyl l ,3,4,5-tetrahydro-2H-3-benzazepin 2-one 3.6 g of the amino acid prepared in Example 1 l wasrefluxed in 36 ml of tetralin under a Dean-Stark trap for 24 hours,after which the solid had dissolved. The cooled solution was dilutedwith 150 ml of petroleum ether (b.p. 6090) and cooled for an hour, thecrystals that separated were recovered by filtration and washed withpetroleum ether. The above-named product was recrystallized fromethanol, m.p. 226227.

EXAMPLE 13 Preparation of dl-2,7,8-Trimethyl-2,3,4,5-tetrahydrol H-3-benzazepine hydrochloride A slurry of 3.7 g of the lactam (0.0182 moles)prepared in Example 12 in 20 ml of tetrahydrofuran was cooled to and 40ml of a 1M solution of borane in tetrahydrofuran gradually added. Afterminutes at 5, almost all of the lactam had dissolved, whereupon themixture was heated to boiling. The clear refluxing solution depositedsome gelatinous material at the liquid-vapor interface after aboutfifteen minutes. Refluxing was continued for another 3 hours, then themixture was cooled in an ice bath and the excess borane cautiouslydecomposed by the dropwise addition of 50 ml of percent hydrochloricacid. The mixture was warmed on the steam bath to boil off the tetrahydrofuran and the cooled residual solution extracted with severalportions of benzene to remove any nonbasic materialfAft er alkalizing topH 1 l, the base was extracted with three 50-ml portions of benzene andone 50-ml portion of ether. The combined extracts were washed withwater, dried (K CO and the solvent distilled in the rotary evaporator.The base was then dissolved in 25 ml of ether and an excess of etherealhydrogen chloride added. The solvent and excess acid were distilled invacuo and the syrupy residue crystallized when rubbed under ethylacetate. This crystalline hydrochloride, of the above named productmelted at 2l9.522l. It was recrystallized from a mixture of ethylacetate and isopropanol and formed white crystals, m.p. 2l82l9.

EXAMPLE 14 In analogy to the procedures described in Example 13, theremay be prepared 7,8-methylenedioxy-2,3,4,5- tetrahydro-lH-3-benzazepine,m.p. 82-84, using the lactam described in paragraph 2 of Example 7.

EXAMPLE 15 Preparation of dl- 1-( 3 ,4-Methylenedioxy-ochloromethylphenyl )-2 acetamido-propane A mixture of 2.21 g ofN-acetyl-amethylhomopiperonylamine (0.01 moles), 6.] ml of 37 percentformaldehyde (0.15 moles) and 20 ml of ethylene chloride was stirred at0-3 while a stream of hydrogen chloride was passed in. After 25 minutes,the suspension was filled with a mass of white crystals that wasfiltered off and washed with ethylene chloride. The solid was slurriedwith several portions of hot acetone to yield the hydrochloride of theabove-named product as a white solid, m.p. l63.5l64.5.

The hydrochloride-free amide, or free base, can be prepared as follows:Alternately the crystalline mass obtained by filtration of thechloromethylation mixture was resuspended in ethylene chloride andsufficient sodium bicarbonate solution added to neutralize the acidity;two homogeneous phases resulted. The organic layer was washed withwater, then dried, and the solvent removed leaving a solid residue. Thiswas recrystallized from isopropanol yielding a crystalline solid, m.p.l32l33; which is the HCl-free amide, i.e., the free base" named above.

The starting material was prepared by refluxing oz-methylhomopiperonylamine with acetic anhydride in toluene for 4.5 hours followed bydistillation of the reaction mixture, N-acetylamethylhomopiperonylaminedistilled at l38l42/0.2 mm as a colorless viscous oil that set to a massof White crystals when rubbed under petroleum ether (b.p. 6090). M.p.9495 after recrystallization from pctroleum ether-ethyl acetate.

EXAMPLE 16 Preparation of dl-N-(6-Cyanomethyl-a-methyl-3,4-methylenedioxyphenethyl )acetamide 26.5 g ofthe amide hydrochloride, (0.087 moles) prepared in Example 15 was addedto 265 ml of DMSO and 25.6 g of sodium cyanide (0.52 moles). Thetemperature rose from 24 to 40', where it was maintained for threehours. The suspension was poured into 1,500 ml of ice water and theresulting mixture extracted three times with 500 ml portions ofchloroform, The

- combined extracts were washed with saturated brine,

then water, dried (MgSO and distilled on the rotary evaporator, leaving20 g of a solid. This solid was first slurried in a 1:1 mixture of ethylacetate and petroleum ether (b.p. 6090) and then recrystallized from 200ml of toluene. After chilling, there was obtained the above-namedproduct in crystalline form, m.p. l34-l35.5.

EXAMPLE 17 Preparation of yellow residue was then refluxed with asolution of 18.8 g of sodium hydroxide (0.408 moles) in 468 ml of 50percent aqueous ethanol for 48 hours. After distilling the bulk of theethanol, the residual solution was acidified to pH 3, whereupon thecrystalline acid separated. The solid was collected by filtration,washed and dried, m.p. 195197. Recrystallization from aqueous ethanolgave crystals of the above-named product, m.p. 197-198.

The hydrolytic mother liquor also contained the deacetylated amino acidwhich precipitated when the pH of the filtrate was adjusted to 7 and thesolution chilled.

EXAMPLE 18 Preparation of dl-4-Methyl-7,8-methylenedioxy-1,3,4,5-tetrahydro- 2H-3-benzazepin-2-one The amino acid together with theresidue that remained on evaporating to dryness the mother liquordescribed in Example 17 were refluxed in 450 ml of tetralin under aDean-Stark trap for 45 minutes and the hot solution filtered frominsoluble material. On cooling, the filtrate deposited crystals. Anequal volume of petroleum ether (b.p. 3060) was added to complete thecrystallization. On filtration, a creamy white crystalline product wascollected. It was washed well with petroleum ether and dried, m.p.177178. Recrystallization from ethyl acetate gave the above-namedproduct as white cottony needles, m.p. l75175.5.

EXAMPLE 19 Preparation ofdl-2-Methyl-7,8-methylenedioxy-2,3,4,5-tetrahydro- 1H-3-benzazepinehydrochloride The cyclic lactam obtained in Example 18 (4.4 g, 0.02moles) in 60 m1. of .tetrahydrofuran was treated with 60 ml. of 1Mborane in tetrahydrofuran at 0. The solid dissolved and the mixture wasrefluxed for three hours after which 100 ml of 3N hydrochloric acid wasadded cautiously and the solution heated on the steam bath until thetetrahydrofuran had distilled. The cooled solution was extracted twicewith 50 ml portions of chloroform to remove unreacted lactam, theaqueous layer then made alkaline, and the base collected by three 50 mlextractions with 1-1 benzene-ether. The extract was washed with water,dried (K CO and the solvent distilled, leaving 3.0 g. of a very paleamber oil. This was dissolved in a mixture of isopropanol-ether and anexcess of ethereal hydrogen chloride added. The resulting creamy whitesolid was collected, washed and dried, m.p. 266268 (dec.). Uponrecrystallization from water, the crystalline hydrochloride of theabove-named product was obtained, m.p. 271.5-272.5 (dec.).

EXAMPLE Chloromethylation of N-Acetylhomoveratrylamine 44.6 g (0.2 mole)of N-acetylhomoveratrylamine, 124 ml of 37 percent formaldehyde, and 400ml of chloroform were mixed and cooled to 15. Hydrogen chloride waspassed into the stirred suspension at -15. As the mixture becamesaturated with HCl crystals began to form and suddenly after about 1.7hours the reaction vessel was filled with a mass of crystals. Thecrystals were transferred to a sintered glass funnel and as much liquidas possible removed by suction; the filter cake was washed twice withchloroform and then transferred to a vacuum dessicator, (20 mm, CaCl andNaOH flakes) where it was brought to constant weight, 50 g, m.p. 139l43.

A sample of this material was recrystallized from ethyl acetate andobtained as clusters of sword-shaped crystals, m.p. 151153 dec withevolution of HCl. This substance is the hydrochloride of N-(6-chloromethy1-3,4-dimethoxyphenethyl)acetamide.

EXAMPLE 2 1 Preparation of 6-( 2-Acetamidoethyl )-4,5-dimethoxyphenylacetonitrile 50 g of the chloromethylated productobtained in Example 20, as the hydrochloride, was added to a stirredsuspension of 20 g of sodium cyanide in 500 ml of dimethylsulfoxide. Thetemperature of the stirred mixture spontaneously rose to 44 during thecourse of 30 minutes and then began to fall. After 1 hr. the mixture waspoured into 1.5 l of ice water and extracted five times with 200-mlportions of chloroform. The chloroform extracts were washed four timeswith saturated brine, dried (MgSO and finally distilled in the rotaryevaporator, leaving a creamcolored solid, m.p. 134l 36.Recrystallization of this solid,. 'from et hyl acetate gave crystals ofthe above-named product, m.p. 138-140.

EXAMPLE 22 Preparation of2-(2-Benzylaminoethyl)-4,S-dimethoxyphenylacetic acid 10.0 g of thenitrile obtained in Example 21 was stirred for one hour with m1 ofethanol saturated with hydrogen chloride, then refluxed for four hours.When cool, the ammonium chloride was removed by filtration and thesolvents distilled from the filtrate leaving 1 1.7 g of a pale amberoil. The oil was not characterized but refluxed with 8.64 g of sodiumhydroxide and ml of 50% aqueous ethanol for 48 hours. This solution wasevaporated to dryness in the rotary evaporator, then dissolved in 36 m1of water and the pH adjusted to 7.0. To this solution, 1.6 g of sodiumhydroxide (0.04 moles) in 8 ml of water was added, followed by 4.24 g ofbenzaldehyde (0.04 moles). After stirring for 15 minutes, the solutionwas distilled to a semisolid in the rotary evaporator. Fifty ml ofisopropanol was added to the residue and the process repeated. Theresidue was dissolved in 200ml of methanol, 2.3 g of sodium borohydride(0.060 moles) added in several portions, then the mixture stirred for0.5 hour. The methanol was distilled in the rotary evaporator, 60 ml ofwater added to the residue and the pH adjusted to 7.5 by the addition of10 percent hydrochloric acid. After chilling in ice for 0.5 hour, thewhite precipitate that had formed was collected, m.p. 2082l0 (turbid).Recrystallization from aqueous ethanol gave the abovenamed product m.p.213213.5.

EXAMPLE 23 Preparation of 3-Benzyl-7 ,8-dimethoxy-1,3,4,5-tetrahydro-2H-3- benzazepin-Z-one A stirred suspension of 4.1 g ofthe benzylamino acid obtained in Example 22 was refluxed in 75 ml. ofxylene under a Dean-Stark trap for 24 hours, at the end of which time aclear solution had resulted. Distillation of the xylene in vacuo leftthe above-named product as shining white plates, m.p. l4ll42. A sampleof the cyclic lactam recrystallized from toluene melted at l4ll42.

EXAMPLE 24 Preparation of 4,5-Methylenedioxy-l,2-bis(chloromethyl)benzene The above-named product was preparedfollowing the procedures of F. Dallacker, K. W. Glombitza and M. Lipp,Liebigs Arm, 643, 67-82 (1961 EXAMPLE 25 Preparation of4,5-Methylenedioxyl ,2-benzenediacetonitrile To a stirred suspension of98 g (2.0 moles) of sodium cyanide in 1.75 l. of dimethylsulfoxide,cooled to l820, 175 g (0.8 moles) of 4,5-methylenedioxy-l ,2-bis(chloromethyl)benzene was added in 1 portion. The temperature roserapidly, but was arrested and maintained at 40 by intermittent coolinguntil it fell spontaneously about 20-30 minutes. The reaction mixturewas poured into 3 l. of ice-water and l l. of chloroform. When the icehad melted, the organic layer was separated and the aqueous layerextracted twice more with 500 ml portions of chloroform. The combinedextracts were washed five times with saturated salt solution (500 mleach), once with water and dried over magnesium sulfate. Distillation ofthe solvent at reduced pressure in the rotary evaporator gave a paleyellow crystalline residue. This solid was recrystallized fromapproximately 2 l. of isopropanol and yielded the above-named product asa cream colored solid, m.p. l05l07.

EXAMPLE 26 Preparation of 2,3 ,4,5-Tetrahydro 7 ,8-methylenedioxy-1H-3-benzazepine l 19 g. (0.595 moles) of 4,5-methylenedioxy-1,2-benzenediacetonitrile was hydrogenated in 2.4 l. of ammonia-saturatedethanol at an initial pressure of 1,000 PSI and 100C in the presence of24 g of Raney nickel for 4 to 5 hours. The cooled autoclave contentswere filtered to remove the nickel, the catalyst washed with 500 ml ofhot ethanol, and the filtrate distilled at reduced pressure, leaving 120g of dark gray oil. This oil was distilled in vacuo using a Claisenstill head and several fractions were collected. The low boilingfractions contained the desired product which upon purification yieldedthe above-named product, m.p. 82-84.

EXAMPLE 27 Preparation of6-Bromo-2,3,4,5,tetrahydro-7,8-methylenedioxy-1H- 3-benzazepinehydrochloride 1 1.65 g of 3-acetyl-2,3,4,5-tetrahydro-7,8-methylenedioxy-lI-I-3-benzazepine was dissolved in 200 ml of acetic acidand to the stirred solution at 55, a solution of 8.3 g (0.053 moles) ofbromine in 75 ml of acetic acid was added during the course of an hour.When about two-thirds of the bromine had been added, a coarseyellow-orange precipitate began to form. This mixture was stirred for 3hours after which time the test for free bromine (starch-potassiumiodide paper) was weak, whereupon the reaction mixture was poured into aliter of cold water and allowed to stand overnight. The precipitate thathad formed was recovered by filtration, washed with water and dried,m.p. l37l 39. A small sample was recrystallized from aqueous ethanol toyield the above-named product as white crystals, m.p. l33l37.

EXAMPLE 28 Preparation of2,3,4,5-Tetrahydro-3-methyl-7,8-methylenedioxyl H- 3-benzazepine 19.1 g(0.1 M) of 2,3,4,5-tetrahydro7,8- methylenedioxy-lH-3-benzazepine basewas dissolved in ml of methanol and 12 ml of 37% formaldehyde (0. 148moles) added thereto. In a few minutes, a new precipitate began to formwith the evolution of heat. To this suspension 5 g of methanol-washedRaney nickel was added and the mixture shaken under 50 lbs. of hydrogenpressure. Uptake of hydrogen was complete in about an hour after whichthe excess hydrogen was vented, the catalyst removed by filtration,washed, and the combined filtrates freed of solvent in the rotaryevaporator. To remove the excess formaldehyde, the residue was dissolvedin 100 ml of benzene, the solution washed four times with water, thendried, and the solvent distilled leaving a syrup. This was distilledfrom a small Claisen flask at reduced pressure, to yield threefractions. The fraction showing a boiling point of l66l67 mm containedthe above-named product.

EXAMPLE 29 Preparation of 3-Ethyl-2,3,4,5-tetrahydro-7,8-methylenedioxyl H-3- benzazepine l 1.68 g (0.05 M)of 3-acetyl-2,3,4,5-tetrahydro-7,8- methylenedioxylI-I-3-benzazepinewas. dissolved in 150 ml of dry tetrahydrofuran (TI-IF) and the solutioncooled to 5. To the stirred solution (under nitrogen) 150 ml of aone-molar solution of borane in THF was added during the course of a fewminutes; no temperature effect was noticeable. After the addition of theborane, the solution was heated to reflux; a gelatinous precipitateappeared soon after the reflux started. After refluxing for 2 hours thereaction vessel was cooled in an ice bath and 100 ml of 3N hydrochloricacid added dropwise to destroy the excess borane and the amineboroncomplex.

After heating under reflux for an hour, the condenser was set fordownward distillation, and the organic solvents removed by distillation.The cooled residue in water was made strongly alkaline, and the baseextracted with three 250-ml portions of benzene. After drying anddistillation of the solvent in the rotary evaporator, there remained apale colored oil. This was dissolved in 20 ml of benzene and thesolution passed over 50 g of A1 0 (I), washing the adsorbent with 300 mlof benzene. Distillation of the solvent left a colorless oil thatrapidly crystallized to yield the above-named product, m.p. 65- 66.

The free base was converted to the hydrochloride in the usual manner andafter recrystallizing from i-PrOl-l- H O it melted at 268269 ('dec).

EXAMPLE 30 Preparation of 3-Allyl-2,3,4,5-tetrahydro-7,8-methylencdioxyl H-3- benzezepine hydrochloride To5.7 g of 2,3,4,5-tetrahydro-7,8-methylenedioxylH-3-benzezepine (0.03moles) in 75 ml of dimethylformamide was added 1.5 g of sodium hydride(0.034 moles). The suspension was stirred at 5560 until no more hydrogenwas evolved. To the suspension, at room temperature, was added 4 g ofallyl bromide in 25 ml of DMF. The suspension was stirred for 8 hours at5560, then at room temperature for a further 12 hours after which it waspoured into 500 ml of water. The suspension was shaken with 100 ml ofbenzene and the layers separated. The benzene layer was washed with NaClsolution and with water. After drying the benzene layer, the solvent wasevaporated to yield the crude crystalline base. A sample wasrecrystallized from 60-90 petroleum ether to yield the abovenamedproduct, m.p. 83.5-85.5".

The above base was converted to the hydrochloride in isopropanol withhydrochloric acid. After one recrystallization from aqueous isopropanol,the m.p. was 267.5268.5(dec).

EXAMPLE 31 Preparation of 3-( 3-Dimethylaminopropyl)-2,3,4,5-tetrahydro-7,8- methylenedioxyl H-3-benzazepine hydrochlorideThe free base was prepared from 1.9 g of 2,3,4,5-tetrahydro-7,8-methylenedioxy-l H-3-benzazepine (0.01 moles), 0.49 g ofsodium hydride (0.01 1 moles), and 2.42 g of 3-dimethylaminopropylchloride in 15 ml of dimethylformamide in the same manner as describedfor 3-allyl-2,3,4,5-tetrahydro-7,8-methylenedioxy-1H- 3-benzazepinehydrochloride. After treating the reac tion mixture with water andextracting with ether (6 X 25 ml) a yellow oil was obtained. This oilwas converted to the hydrochloride and the salt recrystallized fromEtOH-EtOAc twice to yield the abovenamed product as a white solid, m.p.273275 (dec).

EXAMPLE 32 Preparation of 2,3,4,5-Tetrahydro-7 ,S-methylenedioxyl H-3-benzazepine-3-butyric acid hydrochloride A. Preparation of the ethylester of the above-named free base 4.54 g (0.02 mole) of2,3,4,5-tetrahydro-7,8- methylenedioxy-lH-3-benzazepine hydrochloridewas suspended in 40 ml of dry dimethylformamide and to this was added inseveral portions, l.95g (0.042 moles) of a 54% sodium hydride dispersionin mineral oil. On warming to 50-60, hydrogen was evolved and after twohours, the evolution of hydrogen ceased. To this mixture 4.30 g (0.022moles) of ethyl 4'bromobutyrate was added in one portion and the mixturemaintained at 50-60 for another eight hours. The cooled reaction mixturewas poured into 200 ml of ice water and the aqueous phase extracted fourtimes with 50-ml portions of ether. After drying the ether phase (MgSOthe solvent was removed on the rotary evaporator. The oil thus obtainedwas dissolved in l ml of benzene and the solution passed over 50 g of AlO (grade I).

B. Preparation of the amino acid hydrochloride The oil recovered fromthe A1 0 treatment (7 g) was dissolved in 10 ml of ethanol and added toa solution of 1.84 g of sodium hydroxide in 10 ml of water. Afterrefluxing for 4 hours, the alcohol was distilled, the pH of theremaining solution brought to 3, and the solution evaporated to dryness.The solid residue was extracted several times with boiling ethanol andthe combined extracts evaporated to dryness. The residue wasrecrystallized from a mixture of ethanol and ethyl acetate and yieldedafter chilling the above-named product, m.p. 245247 (dec).

EXAMPLE 33 Preparation of 2,3 ,4,5-Tetrahydro-7,8methylenedioxyl H-3-benzazepine-3-acetic acid A. The ethyl ester 45.4 g (0.2 moles) of2,3,4,5-tetrahydro-7,8- methylenedioxy-lH-3-benzazepine hydrochloridewas suspended in 250 ml of dry dimethylformamide. To this was added thesodium hydride obtained by washing the mineral oil from 19.5 g (0.42moles) of a 54% sodium hydride-mineral oil dispersion; 50 ml ofdimethylformamide being used to rinse the hydride into the reactionvessel. The temperature was slowly raised to 50, whereupon hydrogenevolution commenced, and after two hours at 5060 it had practicallyceased. The suspension was cooled in an ice bath and 27.0 g of ethylchloroaeetate added in one portion. The mixture was stirred at 60 for 8hours, then cooled and poured into one I. of ice water. The oil thatseparated was extracted with five 200-ml portions of benzene, thecombined extracts washed with water and dried (MgSO Distillation of thesolvent in the rotary evaporator gave 41 g of dark oil. This oil wasdissolved in 100 ml of benzene and the solution passed over a column of250 g of A1 0 (Woelm I). From the effluent, 20 g of a yellowish oil wasrecovered. Distillation of this oil gave 14 g of pale yellow oil, b.p.l53l64/0.3 mm that rapidly solidified. A small sample was recrystallizedfrom ethanol, to yield 2,3,4,5-tetrahydro-7,8-methylenedioxyl H-3-benzazepine-3-acetic acid ethyl ester, m.p. 8990.

B. 6.0 g of the above ester was refluxed with 30 ml of hydrochloric acidand 90 ml of water for four hours. Distillation of the solvent in therotary evaporator left a residue of white salt. This was recrystallizedtwice from aqueous ethanol to yield the above-named product, m.p.265-267 (dec).

EXAMPLE 34 Preparation of 2,3 ,4,5-Tetrahydro-7,8-methylenedioxylH-3-benzezepine-3-ethanol and the corresponding hydrochloride 6.4 g(0.023 moles) of 2,3,4,5-tetrahydro-7,8-methylenedioxy-lH-3-benzazepine-3-acetie acid ethyl ester in 50 ml ofether was added to a stirred suspension of 2.18 g (0.0575 moles) oflithium aluminum hydride in ml of ether, the entire operation beingconducted in a nitrogen atmosphere. Sufficient heat was evolved to causethe ether to boil, and after the addition was complete, the stirredsuspension was refluxed for another 2 hours. The excess hydride and thecomplex were decomposed with water in the usual way. A few g of filteraid were added to the mixed oxides and the solids removed on a bed offilter aid. Distillation of the ether gave a crystalline residue. Thefilter cake of oxides was refluxed with 100 ml of benzene andrefiltered. From the filtrate, additional crystalline material wasobtained. A sample of the product was recrystallized from petroleumether, b.p. 6090, to yield the above-named product, m.p. 1 l 2l l 3.

The hydrochloride was prepared in the usual manner and afterrecrystallization from isopropanol, it melted at 223-225 (dec).

EXAMPLE 35 Preparation of N ,N-Diethyl-2,3 ,4,5-tetrahydro-7,S-methylenedioxylH-3-benzazepine-3-acetamide hydrochloride 3.8 g of2,3,4,5-tetrahydro-7,8-methylenedioxy-1H- 3-benzazepine (0.02 moles) wassuspended in 50 ml of DMF and the sodium hydride obtained by washing themineral oil from 0.98 g of a 54% dispersion added thereto. The mixturewas heated and stirred at 5560 for 2 hrs, after which hydrogen evolutionceased. To this suspension, 6 g of N,N-diethyl-2-chloroacetamide in 20ml of DMF was added, and the suspension stirred for another eight hoursat '5560. After cooling, the mixture was cautiously treated with water150 ml) and the base recovered by extraction with ether (6 X 75 ml).Distillation of the dried ether extract in the rotary evaporator gave ayellowish oil that was dissolved in anhydrous ether and the resultingsolution acidified with ethereal HCl. The above-named product wasobtained as a white salt by filtration, mp. 23 3-235. After onerecrystallization from EtOAc-iPrOH, the m.p. was 238-240 (dec).

EXAMPLE 37 Preparation of 3-[ 3-(4-Fluorobenzoyl )propyl]-2,3,4,5tetrahydro7,8- methylenedioxyl H-3-benzazepine hydrochlorideThe sodium hydride obtained by washing 1.95 g of the 54% dispersion(0.042 moles) with benzene was used to prepare the sodium salt from 4.54g. of 2,3, 1,5- tetrahydro-7,8-methylenedioxy-1H-3benzazepinehydrochloride in 50 ml of DMF as described in Example 35. Treatment ofthe suspension with 4.41 g of 3-(4 fluorobenzoyhpropyl chloride (0.022moles) for 24 hours at 5560 followed-by decomposition with 200 ml of icewater gave an oil-water suspension. The base was recovered by extractionwith benzene (3 X 50 ml), the combined extracts washed once with water,then dried, and the solvent distilled in the rotary evaporator. To theresidual oil, 3N hydrochloric acid was added and the mixture digestedfor an hour. After cooling the salt was filtered off, mp 195- -197. Twofurther recrystallizations from water gave the above-named product as abuff colored salt, mp 2092l0..

EXAMPLE 37 Preparation of 3Chloroacetyl-2,3,4,5tetrahydro7,8-methylenedioxy l H-3-benzazepine One-tenth mole, 22.7 g, of2,3,4,5-tetrahydro-7,8- methylenedioxy-lH-3-benzazepine was dissolved in200 ml of water and 200 ml of benzene added. Forty ml of a 10%.solutionof sodium hydroxide was added to the vigorously stirred-emulsion and 17g (0.15 mole) of chloroacetyl chloride was added dropwise. As'the pHapproached 5, another l-ml portion of sodium hydroxide solution wasadded until a total of ml had been added. After all the chloroacetylchloride had been added, the mixture, which had an acid reaction, wasstirred for another 10 minutes then allowed to stand overnight at roomtemperature.

The mixture of solid and two liquid phases was filtered to recover thesolid; it was washed with water and air dried. The benzene solution wasseparated, washed to neutrality with water, driedl, and the solventremoved in the rotary evaporator.

The solids were combined and recrystallized from approximately 300 ml ofisopropanol. After standing overnight at room temperature, the mixturewas cooled in an ice bath for three hours. The crystals that separatedwere filtered off, washed with a little isopropanol and dried to yieldthe above-named product, rn.p. l25l26.5.

EXAMPLE 38 Preparation of 2,3,4,5-Tetrahydro-3-mcthylaminoacetyl-7,8methylenedioxyl l-l-3-beinzazepine hydrochloride 13.5 g (0.05 mole)of 3-chloroacetyl-2,3,4,5-tetrahydro-7,8-methylenedioxy-lH-3-benzazepine was dissolved in 250 m1of dry tetrahydrofuran and the solu tion added to approximately ml ofliquid methylamine at 78. The mixture was stirred for 20 hours allowingthe temperature to rise to 22 during this interval after which it waswarmed on the steambath to drive out the excess mcthylamine. The whitesolid that had formed was filtered off and washed with tetrahydrofuran.Distillation of the solvent in the rotary evaporator left 18.2 g of athick yellow syrup which was dissolved in a minimum of hot isopropanol.Chilling gave a white salt, mp 250252 dec. The salt was dissolved in 30ml of hot methanol, the solution filtered and diluted with 210 ml ofethyl acetate. On standing at room temperature white crystals of theabove-named product separated, mp 253254(dec.).

EXAMPLE 39 Preparation of 3[2-( a, a,a-Trifluoro-m-tolyl )acetyl ]-2,3,4,5tetrahydro-7,8- methylenedioxyl H-3-benzazepine 6.0 g ofa,aa-trifluoro-m-tolyl acetyl chloride (0.027 moles) was dissolved in 50m1 of dry benzene and added dropwise to a stirred solution of 2,3,4,5-tetrahydro-7,8-methylenedioxy lH-3-benzazepine, 12.8 g (0.067 mole) in50 ml of benzene at T 40. After 30 minutes of stirring the suspension ofwhite crystals, the mixture was transferred to a separatory funnel,washed several times with water, the organic phase dried.

(MgSO and then distilled'in the rotary evaporator. The crude solid wasrecrystallized from 6090 petroleum ether to give the above-namedproduct, mp l02-104.

EXAMPLE 40 Preparation of N-( 3 ,4-Methylenedioxyphenetyl )phthalimideForty-one g of 3,4-methylenedioxyphenethylamine (0.25 moles) wasrefluxed with 36 g of phthalic anhydride (0.28 moles) and 65ml. ofacetic acid for 2.5 hours. The mixture was cooled whereupon itsolidified. The solid mass was broken up and triturated with water andthe solid recovered by filtration. Recrystallization from 300 ml ofacetic acid and 125 ml of water gave white crystals of the above-namedproduct, m.p. 139140.5.

EXAMPLE 41 Preparation of N-[ 3-( 3 ,4Dimethoxyphenyl)propyllphthalimide 6.4 g of 3-(3,4-dimethoxyphenyl)-propylamine (0.03moles) was refluxed with 5.47 g of phthalic anhydride (0.037 moles) in70 ml of acetic acid for 2.5 hours. the solvent was then removed in therotary evaporator. Recrystallization of the residue from 150 ml of ethergave 4.0 g of a first crop, m.p. 8285 and 7.0 g of a second crop, m.p.81-83.

EXAMPLE 42 Preparation of 2-( 3-Phathalimidepropyl )-4,5dimethoxybenzylchloride 3.25 g of N-[3-(3,4-dimethoxyphcnyl)propyljphtholimide (0.01mole) was dissolved in 28 ml of chloroform and 2.25 g ofparaformaldehyde (0.075 moles) added thereto along with 0.6 ml ofconcentrated hydrochloric acid. the mixture was vigorously stirred at-20 to 25 as a stream of hydrogen chloride was passed through. After twohours the mixture, which consisted of two liquid phases, was poured into40 ml of ice water, the chloroform phase removed, and the aqueous layerextracted once with 20 ml of chloroform. the combined chloroform layerswere washed three times with 40 ml portions of ice water, dried, and thesolvent distilled in the rotary evaporator. the solid residue wasrecrystallized from a mixture of ethyl acetate/petroleum ether (6090) toyield the above-named product, m.p. 1509-1533 EXAMPLE 437,8-Methylenedixoy-2,3,4,5-tctrahydro-1H-3- benzazepine was prepared inthe form of several pharmacological formulations as follows:

A. Tablet Formulation benzazepine, lactose, corn starch, and Amijel B011 were blended in a suitable mixer.

2. The mixture was granulated to a heavy paste with water and the moistmass was passed through a No. 12 screen. It was then dried overnight at1 F.

3. The dried granules were passed through a No. 16

screen and transferred'to a suitable mixer. The calcium stearatewasadded and mixed until uniform.

4. The mixture was compressed at a tablet weight of 410 mg. using tabletpunches having a diameter of approximately three-eighths inch. (Tabletsmay be either flat or biconvex and may be scored if desired.) *Aprehydrolyzed food grade corn starch. Any similar prchydrolyzcd cornstarch may be used. Purchased from: Corn Products Company 10 East 56thStreet New York, New York B. Tablet Formulation Per Tablet7.8-Methylenedioxy- 2 3,4,5-tetrahydrolH-3-henzazepine 25.00 mg.Dicalcium Phosphate 175.00 mg. Dihydrate Unmilled Corn Starch 24.00 mg.Magnesium Stearate 1.00 mg. Total Weight 225.00 mg.

Procedure 1. 7,8-Methylenedioxy-2,3 ,4,5-tetrahydro-1H-3- benzazepineand corn starch were mixed together and passed through an No. 00 screenin Model J Fitzmill with hammers forward.

2. This remix was then mixed with dicalcium phosphate and one-half ofthe magnesium stearate, passed through a No. 1A screen in Model JFitzmill with knives forward, and slugged.

3. The slugs were passed through a No. 2A plate in a Model D Fitzmill atslow speed with knives forward, and the remaining magnesium stearate wasadded.

4. The mixture was mixed and compressed.

C. Capsule Formulation Per Capsule 7,8-Methylenedioxy-2.3.4.5-tetrahydrolH-3 ben7.azepine 50 mg.

Lactose, U.S.P. mg.

Corn Starch, U.S.P. 30 mg. Talc, U.S.P. 5 mg. Total Weight 210 mg.

Procedure:

1 7,8-Methylenedioxy-2,3 ,4,5-tetrahydrol H-3- benzazepine was mixedwith lactose and corn starch in a suitable mixer.

2. The mixture was further blended by passing through a FitzpatrickComminuting Machine with a No. 1A screen with knives forward.

3. The blended powder was returned to the mixer,

the tale added and blended thoroughly.

4. The mixture was filled into No. 4 hard shell gelatin capsules on aParke Davis capsulating machine.

D. Capsule Formulation Per Capsule 7-8-Methylenedioxy- 23,4,5-tetrahydrolH-3-benzazepinc 10 mg. Lactose, U.S.P. mg. Corn Starch,U.S.P. 30 mg. Talc. U.S.P. 5 mg.

Total Weight 210 mg.

Procedure 1. 7,8-Methylenedioxy-2,3,4,5-tetrahydro- 1 1-1-3- benazepine,lactose and corn starch were mixed in a suitable mixer.

2. The mixture was further blended by passing through a FitzpatrickComminuting Machine with a No. 1A screen with knives forward.

3. The blended powder was returned to the mixer,

the tale added and blended thoroughly.

4. The mixture was filled into No. 4 hard shell gelatin capsules on aParke Davis capsulating machine. (Any similar type capsulating machinemay be used).

EXAMPLE 44 The formulations of Example 43 were repeated usmg:

2,3,4,5-tetrahydro-3-methyl-7,8-methylenedioxylH-3-benzazepine; and3-ethyl-2,3 ,4,5-tetrahydro-7,8-methylenedioxy-1H- 3-benzazepine. Weclaim: l. A process for the preparation of compounds of the formulawherein R and R each independently signify lower alkoxy, or takentogether signify methylenedioxy; R signifies hydrogen, lower alkyl,carboxy, aryl, or ary substituted by a member selected from the groupconsisting of halogen, lower alkyl, nitro, or trifluoromethyl; and N isI or 2 which comprises:

A. reacting a compound of the formula wherein R 41 and n are asdescribed above and X signifies a suitable protecting group selectedfrom the group consisting of acyl and phthaloyl groups, withformaldehyde and hydrogen chloride in an inert or ganic solvent toobtain a compound of the formula wherein R 42 X and n are as describedabove;

B. treating the above-obtained product with an alkali metal cyanide toobtain a compound-of the formula NH-X CHZCN wherein R -R X and n are asdescribed above;

C. Refluxing the above-obtained product in absolute alcohol andanhydrous acid with the subsequent addition of water to obtain acompound of the formula (CHi fRi NHX CH. ,COOEt wherein R- ,R X and nare as described above;

D. Treating the above-obtained product in an aquewherein R R X and n areas described above;

E. removing the protecting group from the aboveobtained product toobtain a compound of the formula wherein R R. and n are as describedabove;

F. condenslng the above-obtained product to obtain a compound of theformula UNITED STATES PA'IIINT OFFICE C E RTI FlCATE O F CORRECTIONPatent N0- Dated September L6 Inventoflg) Arnold Brossi, BenjaminPecherer and Robert Sunbury It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 25, line 37, the word "ary" should be aryl Signed and Scaled thisThirty-first Day of August 1976 AUCSI.

RUTH C. MASON C. MARSHALL DANN Arresting Officer (ommissinner of Patentsand Trademarks

1. A PROCESS FOR THE PREPARATION OF COMPOUNDS OF THE FORMULA